Torsemide, chemically named N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl) amino]-3-pyridinesulfonamide III, is a loop diuretic which has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
The synthesis of torsemide is described in prior art documents including: Delarge et al, Ann. Phann. Fr.31, 467-474 (1973); Delarge et al, Mem. Acad. R. Med. Belg. 47(3), 131-210 (1974); DE 2,516,025 ; U.S. Pat. No. 4,244,950; U.S. RE 30,633; and WO 03/097603 all of which are incorporated herein by reference.
A common process for the preparation of the torsemide III from 4-chloro-3-pyridinesulfonamide I, via intermediate 4-[(3-methylphenyl)amino]-3-pyridinesulfonamide II is depicted in scheme 1 below.

U.S. RE 30,633 (1981, A. Christiaens Societe Anonyme, Belgium) disclose such a synthetic route to torsemide III and an intermediate II. For the preparation of II, the reaction is carried out in the presence of copper powder and at elevated temperature. The purification procedure of II is laborious as well in U.S. RE 30,633. Generally, it is disadvantageous to employ a heavy metal (such as copper) in the later stages of active pharmaceutical ingredient (API) production. Additional purification steps may be required to remove residual traces of the heavy metal from the API or its precursor.
U.S. RE 30,633 further provides for the preparation of torsemide III by the subsequent reaction of 4-[(3-methylphenyl)amino]-3-pyridinesulfonamide II with isopropyl isocyanate in the presence of triethylamine. The solvent system used in U.S. RE 30,633 is dichloromethane, dioxane or neat (i.e. no solvent added). After evaporative removal of the solvent, the mixture is clarified in aqueous sodium carbonate and further addition of acetic acid to furnish torsemide III.
Under such conditions the desired product, torsemide III is isolated in low yields with a high percentage of impurities, thus requiring additional purification steps.
U.S. Pat. No. 6,635,765 (Teva, 2001) discloses a process for preparing torsemide III comprising the step of reacting 3-sulfonamide-4-(3′-methylphenyl)aminopyridine II with isopropyl isocyanate in the presence of triethylamine in a solvent selected from the group consisting of acetonitrile, acetone, ethyl acetate, butyl acetate and mixtures thereof. Upon reaction completion, the pH is adjusted to 4.3 using aqueous hydrogen chloride solution and the precipitated product is isolated by filtration. It is then further purified by trituration in a mixture of acetonitrile and water. Thus, crude torsemide III is obtained with a purity of more than 98% and a chemical yield of 81.5%. In this process, once acidified, a large amount of water has to be added to precipitate the product III. However, many other organic impurities, including the toxic and difficult to remove N,N′-isopropyl urea (from the isopropyl isocyanate), precipitate out as well.
WO 03/097603 (Finetech Laboratories Ltd., 2003) discloses a process for manufacturing torsemide III. However, the process includes the use of isopropyl carbamate. This is not a commercially available compound and is prepared from the toxic and difficult to handle reagent, phenylchloroformate.
Furthermore, excessive exposure to carbamates has been shown to cause fatigue, joint and muscle pain and headaches. Additionally, laboratory experiments indicate that some carbamates have mutagenic or carcinogenic properties.
Furthermore, although WO 03/097603 describes a synthesis for the manufacture of the intermediate II where copper is absent, based on Example 11 the solvent used is methyl ethyl ketone and the reaction does not go to completion. The yield is 91.4% and the purity is only 99.0%, with 0.5% of the 4-chloro-3-pyridine sulfonamide starting material still present.
Once again, the torsemide III is isolated in low yields with an impurity level of toxic material that is difficult to remove.
In summary, some of the disadvantages of the prior art processes include:                i) the purity of the isolated torsemide is low thereby requiring additional steps to obtain pharmaceutically acceptable substance;        ii) the chemical yield of 81.5% for the crude torsemide is low;        iii) because water is introduced to isolate the torsemide during the acidification step, the torsemide is contaminated with N,N′-isopropyl urea;        iv) potential carcinogenic or mutagenic isocarbamate is used;        v) heavy metal usage requires removal thereof, which is difficult.        
The yields of the prior art processes are low, highly variable and are unsuitable when transiting to commercial production.
It is therefore necessary to overcome the deficiencies of the prior art and to develop a cost-effective, robust and scalable process to manufacture both torsemide III and torsemide intermediate II. A further objective is to develop a process for making torsemide III meeting the high purity specifications required for an API.
Further and other objects of the invention will become apparent to a person skilled in the art when reading the following.